CA3144770A1 - Stereoisomers of the compound 3-(benzo[d][1,3]dioxol-5-yl)-7-(1-hydroxypropan-2-yl)-1-(1h-indol-3-yl)-6,7-dihydro-3h-oxazol[3,4-a]pyrazine-5,8-dione and use thereof as an antitumor agent and phosphodiesterase enzyme inhibitor - Google Patents
Stereoisomers of the compound 3-(benzo[d][1,3]dioxol-5-yl)-7-(1-hydroxypropan-2-yl)-1-(1h-indol-3-yl)-6,7-dihydro-3h-oxazol[3,4-a]pyrazine-5,8-dione and use thereof as an antitumor agent and phosphodiesterase enzyme inhibitor Download PDFInfo
- Publication number
- CA3144770A1 CA3144770A1 CA3144770A CA3144770A CA3144770A1 CA 3144770 A1 CA3144770 A1 CA 3144770A1 CA 3144770 A CA3144770 A CA 3144770A CA 3144770 A CA3144770 A CA 3144770A CA 3144770 A1 CA3144770 A1 CA 3144770A1
- Authority
- CA
- Canada
- Prior art keywords
- benzo
- dihydro
- hydroxypropan
- pyrazine
- dione
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 103
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 title claims abstract description 11
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 title claims abstract description 11
- 239000002532 enzyme inhibitor Substances 0.000 title abstract description 6
- 229940125532 enzyme inhibitor Drugs 0.000 title abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 title description 4
- 239000000203 mixture Substances 0.000 claims abstract description 62
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 24
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims abstract description 13
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims abstract description 13
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 9
- 229940002612 prodrug Drugs 0.000 claims abstract description 7
- 239000000651 prodrug Substances 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 150000002148 esters Chemical class 0.000 claims abstract description 6
- 150000004677 hydrates Chemical class 0.000 claims abstract description 5
- 239000012453 solvate Substances 0.000 claims abstract description 5
- -1 benzo [d] [1, 3] dioxol-5-yl Chemical group 0.000 claims description 40
- 238000011282 treatment Methods 0.000 claims description 26
- SFDGJDBLYNJMFI-UHFFFAOYSA-N 3,1-benzoxazin-4-one Chemical compound C1=CC=C2C(=O)OC=NC2=C1 SFDGJDBLYNJMFI-UHFFFAOYSA-N 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 230000005764 inhibitory process Effects 0.000 claims description 11
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- 239000004480 active ingredient Substances 0.000 claims 2
- 238000011321 prophylaxis Methods 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 238000005481 NMR spectroscopy Methods 0.000 description 16
- 239000007787 solid Substances 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 125000005605 benzo group Chemical group 0.000 description 12
- 208000010228 Erectile Dysfunction Diseases 0.000 description 10
- 201000001881 impotence Diseases 0.000 description 10
- 238000003556 assay Methods 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 230000001028 anti-proliverative effect Effects 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 6
- 230000004663 cell proliferation Effects 0.000 description 6
- 230000004927 fusion Effects 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 201000010099 disease Diseases 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- 206010005003 Bladder cancer Diseases 0.000 description 4
- 101100189582 Dictyostelium discoideum pdeD gene Proteins 0.000 description 4
- 101150098694 PDE5A gene Proteins 0.000 description 4
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 102100029175 cGMP-specific 3',5'-cyclic phosphodiesterase Human genes 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 4
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 4
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 4
- 230000007928 solubilization Effects 0.000 description 4
- 238000005063 solubilization Methods 0.000 description 4
- 229960000835 tadalafil Drugs 0.000 description 4
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 description 4
- 201000005112 urinary bladder cancer Diseases 0.000 description 4
- 238000002424 x-ray crystallography Methods 0.000 description 4
- BKMMTJMQCTUHRP-GSVOUGTGSA-N (2r)-2-aminopropan-1-ol Chemical compound C[C@@H](N)CO BKMMTJMQCTUHRP-GSVOUGTGSA-N 0.000 description 3
- BKMMTJMQCTUHRP-VKHMYHEASA-N (S)-2-aminopropan-1-ol Chemical compound C[C@H](N)CO BKMMTJMQCTUHRP-VKHMYHEASA-N 0.000 description 3
- 239000002249 anxiolytic agent Substances 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 235000011148 calcium chloride Nutrition 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000002875 fluorescence polarization Methods 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229960003310 sildenafil Drugs 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 229940124549 vasodilator Drugs 0.000 description 2
- 239000003071 vasodilator agent Substances 0.000 description 2
- RQFCJASXJCIDSX-UHFFFAOYSA-N 14C-Guanosin-5'-monophosphat Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(COP(O)(O)=O)C(O)C1O RQFCJASXJCIDSX-UHFFFAOYSA-N 0.000 description 1
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- 208000015924 Lithiasis Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 description 1
- 244000126002 Ziziphus vulgaris Species 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- RQFCJASXJCIDSX-UUOKFMHZSA-N guanosine 5'-monophosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O RQFCJASXJCIDSX-UUOKFMHZSA-N 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000000297 inotrophic effect Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
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- 239000012488 sample solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 229960002381 vardenafil Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201962874321P | 2019-07-15 | 2019-07-15 | |
| US62/874,321 | 2019-07-15 | ||
| PCT/BR2020/050259 WO2021007636A1 (pt) | 2019-07-15 | 2020-07-14 | Estereoisômeros do composto 3-(benzo[d][1,3]dioxol-5-il)-7-(1-hidroxipropan-2-il)-1-(1 h-indol-3-il)-6,7-dihidro-3 h-oxazol[3,4-a]pirazina-5,8-diona e seu uso como antitumoral e inibidor da enzima fosfodiesterase |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA3144770A1 true CA3144770A1 (en) | 2021-01-21 |
Family
ID=74209603
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA3144770A Pending CA3144770A1 (en) | 2019-07-15 | 2020-07-14 | Stereoisomers of the compound 3-(benzo[d][1,3]dioxol-5-yl)-7-(1-hydroxypropan-2-yl)-1-(1h-indol-3-yl)-6,7-dihydro-3h-oxazol[3,4-a]pyrazine-5,8-dione and use thereof as an antitumor agent and phosphodiesterase enzyme inhibitor |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US20220296590A1 (ko) |
| EP (1) | EP4001282A4 (ko) |
| JP (1) | JP2022540866A (ko) |
| KR (1) | KR20220035048A (ko) |
| CN (1) | CN114158266A (ko) |
| AR (1) | AR119407A1 (ko) |
| BR (1) | BR112021024894A2 (ko) |
| CA (1) | CA3144770A1 (ko) |
| IL (1) | IL288971A (ko) |
| MX (1) | MX2021015425A (ko) |
| WO (1) | WO2021007636A1 (ko) |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3635178A (en) | 1970-04-17 | 1972-01-18 | Home Curtain Corp | Machine for making shirred curtains |
| US5250534A (en) | 1990-06-20 | 1993-10-05 | Pfizer Inc. | Pyrazolopyrimidinone antianginal agents |
| GB9401090D0 (en) | 1994-01-21 | 1994-03-16 | Glaxo Lab Sa | Chemical compounds |
| WO1999011279A1 (en) | 1997-09-04 | 1999-03-11 | Rexall Sundown, Inc. | Composition and method for the treatment of benign prostatic hyperplasia and prostatitis |
| UY33535A (es) * | 2010-08-13 | 2011-12-01 | Biolab Sanus Farmaceutuca Limitada | Derivados de 6,7-dihidro-3h-oxazolo[3,4]pirazin-5,8-diona |
| US8673914B2 (en) * | 2011-03-28 | 2014-03-18 | St. John's University | Use of phosphodiesterase inhibitors for treating multidrug resistance |
| AR099523A1 (es) | 2014-02-24 | 2016-07-27 | Biolab Sanus Farmacêutica Ltda | Compuestos derivados de 6,7-dihidro-3h-oxazolo[3,4-a]pirazina-5,8-diona |
| WO2019130052A1 (en) * | 2017-12-26 | 2019-07-04 | Ftf Pharma Private Limited | Liquid oral formulations for pde v inhibitors |
-
2020
- 2020-07-14 WO PCT/BR2020/050259 patent/WO2021007636A1/pt unknown
- 2020-07-14 BR BR112021024894A patent/BR112021024894A2/pt unknown
- 2020-07-14 CN CN202080051067.1A patent/CN114158266A/zh active Pending
- 2020-07-14 JP JP2022502020A patent/JP2022540866A/ja active Pending
- 2020-07-14 MX MX2021015425A patent/MX2021015425A/es unknown
- 2020-07-14 US US17/626,635 patent/US20220296590A1/en active Pending
- 2020-07-14 KR KR1020217043172A patent/KR20220035048A/ko unknown
- 2020-07-14 CA CA3144770A patent/CA3144770A1/en active Pending
- 2020-07-14 EP EP20839690.3A patent/EP4001282A4/en active Pending
- 2020-07-15 AR ARP200101981A patent/AR119407A1/es unknown
-
2021
- 2021-12-13 IL IL288971A patent/IL288971A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BR112021024894A2 (pt) | 2022-01-25 |
| AR119407A1 (es) | 2021-12-15 |
| IL288971A (en) | 2022-02-01 |
| CN114158266A (zh) | 2022-03-08 |
| US20220296590A1 (en) | 2022-09-22 |
| JP2022540866A (ja) | 2022-09-20 |
| WO2021007636A1 (pt) | 2021-01-21 |
| EP4001282A4 (en) | 2023-07-19 |
| EP4001282A1 (en) | 2022-05-25 |
| MX2021015425A (es) | 2022-02-21 |
| KR20220035048A (ko) | 2022-03-21 |
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